OBJECTIVE Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group<\/p>\n
3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E (eIF4E), a critical mediator<\/p>\n
of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription.<\/p>\n
Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and<\/p>\n
EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap<\/p>\n
between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing<\/p>\n
ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma.<\/p>\n
METHODS Multiple in vitro assays were performed using human ONS-76 (a primitive SHH model) and D425 (an aggressive<\/p>\n
group 3 model) cells. The impacts of ribavirin on cellular growth, death, migration, and invasion were quantified<\/p>\n
using proliferation and Cell Counting Kit-8 (CCK-8) assays, flow cytometry with annexin V (AnnV) staining, scratch<\/p>\n
wound assays, and Matrigel invasion chambers, respectively. Survival following daily ribavirin treatment (100 mg\/kg) was<\/p>\n
assessed in vivo in immunodeficient mice intracranially implanted with D425 cells.<\/p>\n
RESULTS Compared to controls, ribavirin treatment led to a significant reduction in medulloblastoma cell growth<\/p>\n
(ONS-76 proliferation assay, p = 0.0001; D425 CCK-8 assay, p < 0.0001) and a significant increase in cell death (flow<\/p>\n
cytometry for AnnV, ONS-76, p = 0.0010; D425, p = 0.0284). In ONS-76 cells, compared to controls, ribavirin significantly<\/p>\n
decreased cell migration and invasion (Matrigel invasion chamber assay, p = 0.0012). In vivo, ribavirin significantly<\/p>\n
extended survival in an aggressive group 3 medulloblastoma mouse model compared to vehicle-treated controls (p =<\/p>\n
0.0004).<\/p>\n
CONCLUSIONS The authors demonstrate that ribavirin, a clinically used drug known to inhibit eIF4E and EZH2, has<\/p>\n
significant antitumor effects in multiple preclinical models of medulloblastoma, including an aggressive group 3 animal<\/p>\n
model. Ribavirin may represent a promising targeted therapeutic in medulloblastoma.<\/p>\n
(DOI: 10.3171\/2020.8.PEDS20561)<\/p>\n","protected":false},"excerpt":{"rendered":"
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